MITOCHONDRIAL DISEASE-ASSOCIATED WITH THE T8993G MUTATION OF THE MITOCHONDRIAL ATPASE-6 GENE - A CLINICAL, BIOCHEMICAL, AND MOLECULAR STUDYIN 6 FAMILIES

Aim-To contribute to the establishment of a rational clinical, neurora diological, and molecular approach to neurogenic muscle weakness, atax ia, and retinitis pigmentosa (NARP) and maternally inherited Leigh's s yndrome (MILS). Methods and results-The T8993G mutation in the mitocho ndrial genome was found in several maternal members of six pedigrees, whose clinical status ranged from no symptoms to severe infantile suba cute necrotising encephalomyelopathy (Leigh's disease). In one case a MELAS-like syndrome was documented both clinically and neuroradiologic ally. Relevant genetic features of the series were anticipation of sym ptoms through subsequent generations, and the presence of several case s in whom the mutation apparently occurred recently or was new. A unif orm distribution of the mutation in many tissues was shown in one pati ent subjected to necropsy. In general, a good correlation was found be tween clinical severity and mutation heteroplasmy in readily accessibl e tissues, such as lymphocytes or fibroblasts. By contrast, a consiste nt reduction of the mitochondrial ATPase activity, to about half of th e normal values, was found in most of the clinically affected cases, i rrespective of the amount of mutant mitochondrial DNA. Conclusions-Alt hough the measurement of ATP hydrolysis in cultured fibroblasts was a reliable, and sometimes instrumental, means to identify T8993G positiv e patients, the relation between the mutation and the oxidative phosph orylation defect is probably very complex, and its understanding requi res more complex biochemical analysis.